We have demonstrated that the onset of insulin resistance is temporally related to the development of hepatic steatosis, an early histologic feature of ALD, thus linking hepatic steatosis with the pathogenesis of ALD. Hepatic steatosis results from several perturbations of lipid metabolism including direct and indirect cellular injury and impairment of key lipid homeostatic pathways. The histologic focal point of hepatic steatosis is the intrahepatic lipid droplet, a dynamic organelle now recognized to have critical functions in cellular lipid homeostasis. Lipid droplets are comprised of cores of mostly neutral lipids surrounded by a phospholipid monolayer of lipids, metabolically active NS 5806 enzymes, and lipid droplet proteins. The Perilipin family of lipid droplet proteins associates with the phospholipid monolayer and we and others have shown that these proteins have roles in both lipid and glucose homeostasis in cell culture and animal models of non-alcoholic fatty liver disease. The role lipid droplet biology plays in the pathogenesis of ALD, however, is not well understood. In the liver, Perilipin 2 is the most abundant lipid droplet protein; while Perilipin 3 is mildly expressed and Perilipin 1 is de novo expressed in non-alcoholic steatohepatitis. Plin2 is found in steroidogenic and metabolically active cells ; reduces the turnover of triglyceride ; and regulates fatty acid metabolic enzymes. Furthermore, we and others have shown that Plin2 deficiency protects against diet-induced obesity and insulin resistance. The specific role of Plin2 in ALD is not known. In ALD rodent models, Plin2 is increased in the livers of mice and rats chronically fed alcohol. We recently reported that the increase in hepatic Plin2 is twice that of mice fed a control-liquid diet and the upregulation of Plin2 temporally TC Mps1 12 coincides with the onset of hepatic steatosis, glucose intolerance and increase in hepatic ceramides. These findings are independent of changes in energy intake and expenditure and therefore suggest an interaction between Plin2 and alcohol in lipid and glucose dysregulation. In the present study, we aimed to determine whether an absence of Plin2 prevents the development of hepatic steatosis in alcohol-fed mice. We further sought to elucidate the interactions of alcohol and Plin2 on energy, glucose and lipid homeostasis. A key feature of ALD is impaired hepatic lipid metabolism.